"Fluoride is known to affect mineralizing tissues,
but effects upon the developing brain have not been previously
considered....Fluoride exposures caused sex-specific and dose-specific
behavioral deficits with a common pattern...the severity of the effect on
behavior increased directly with plasma fluoride levels and fluoride
concentrations in specific brain regions...such associations are important
considering that plasma levels in rats...are similar to those reported in
humans...

There have been reports from Chinese investigators that
high levels of fluoride (3ppm+) affect the nervous system directly without
first causing skeletal fluorosis. One study of adult humans found
attention affected 100ppm of sodium fluoride, an exposure level
potentially relevant to humans because toothpastes contain from 1000 to
1500 ppm fluoride, and mouthrinses contain 230-900 ppm fluoride."

"In fact, effects on behavior related directly to
plasma fluoride levels and the fluoride accumulation in the brain. This
contradicts findings from short-term kinetic studies, which found that the
adult blood-brain barrier was "relatively impermeable to
fluoride" when the whole-brain fluoride levels were measured within
one hour. Considering the brain fluoride accumulations found in this
study, such "impermeability" does not apply to chronic exposure
situations"

"The hyperactivity and cognitive deficits are
generally linked with hippocampal damage, and in fact, the hippocampus us
considered to be the central processor which integrates inputs from the
environment, memory, and motivational stimuli to process behavioral
decisions and modify memory. [Delong,G.R.,Autism, amnesia, hippocampus and
learning,Neuroscientific and Behavioral Review, 16:653-70, 1992]"

"Hippocampal selectivity was disrupted when adult
females were exposed for 6 weeks to 100 ppm fluoride (toothpaste is ten
times stronger); hippocampal fluoride levels increased and behavior was
affected. Overall, the behavioral changes from fluoride exposure are
consistent with interrupted hippocampal development....this is the first
laboratory study to demonstrate that central nervous system functional
output is vulnerable to fluoride, and that the effects on behavior depend
on age at exposure and that fluoride accumulates in brain tissues.
Experience with other developmental

neurotoxicants prompts expectations that changes in
behavioral function will be comparable across species, especially humans
and rats. Of course, behaviors per se do not extrapolate, but a generic
behavioral disruption as found in this rat study can be indicative of a
potential for motor dysfunction, IQ deficits and/or learning disabilities
in humans. Substances that accumulate in brain tissues potentiate concerns
about neurotoxic risks."

Investigations into the Role of the Hippocampus

See also: Two Component Functions of the
Hippocampal Memory System and On The Neural Mechanisms of Sequence
Learning and The Neurobiology of Adaptation [with graphics], and
understand that if fluorides severely impact and damage the hippocampus,
what is that neurologically and behaviorally doing to the population in
terms of their response-ability and perception? These articles will give
you a clue, considering that fluorides do not prevent caries, what
fluorides are really being used for, and why the U.S. government is
pushing it so hard.

The Role of Hippocampal Structures in the Organization
of Memory Representations

In addition to its role in extending the persistence of
memory representations many investigators have also suggested that the
hippocampus is critical for only one kind of memory or one form of memory
representation. In humans, there is considerable agreement that the
hippocampal region is critical specifically for declarative memory, the
capacity for conscious and explicit recollection. By contrast, the
acquisition of biases or adaptations to individual items, engaged through
repetition of the learning event and revealed typically by implict
measures of memory, is intact following hippocampal damage. To study the
representational features of hippocampal-dependent memory in animals we
have focused on two characteristic performance capacities associated with
declarative memory: the ability to store and remember relationships among
perceptually distinct items and the ability to express these memories
flexibly in novel situations. Furthermore, as in our studies on the
olfactory cortex, this work involves performance in learning and
remembering relationships between odor stimuli as a prototypical example
of declarative memory processing. In attempting to understand the neural
mechanisms that underlie learning-stimulus relations it is important to
consider two general ways by which stimulus representations could become
bound to one another.

In his classic considerations of the "binding
problem" in perception and memory, William James suggested that
stimuli may either be conceived as not distinct from one another and
consequently might be bound by a conceptual fusion or, alternatively,
might be discriminated as separate and then bound by association in
memory. Indeed these two forms of stimulus binding can be distinguished in
the performance of human amnesics.

Amnesics are typically impaired in learning new
associations, but with extra effort they do sometimes succeed. In these
cases the associations appear to be too well bound such that amnesics find
it abnormally difficult to express memory for the original elements of a
successfully acquired association when the elements are subsquently
separated. Such associations are characterized as "hyperspecific"
in that they can be expressed only in highly constrained conditions that
imitate the conditions of original learning. For example, in one
experiment that involved learning baseball facts in a qucstion-and-answer
format, a densely amnesic subject could correctly recall answers only if
the test procedure included precise repetitions of the original questions
used during learning.

Hyperspecificity of associations has also been observed
in animals with damage to the hippocampal system. For example, in our own
previous work we found that rats with damage to the hippocampal system
were abnormally inclined to bind together the representations of stimuli
that were closely juxtaposed in olfactory or spatial learning . These rats
were able to perform odor-discrimination problems when they had to choose
between two discriminative cues presented in frequently experienced
pairings but, unlike normal rats, they could not recognize the same
stimuli in probe trials that involved novel pairings of familiar odor cues
taken from different discrimination problems. Similarly. we found that
rats with hippocampal system damage could learn to use distal spatial cues
to locatc an escape platform in the Morris water maze when they were
allowed to begin trials from a consistent starting point, but unlike
normal rats, they could not use these same cues to navigate to the escape
locus in probe trials where they had to view those familiar stimuli from
novel starting points in the maze. Our interpretation of this data is that
amnesia associated with damage to the hippocampal system distinguishes
between Jamesą two forms of binding; amnesics are abnormally inclined to
fuse rather than distinguish and associate items.

These considerations led us to examine the role of the
hippocampal system in a classic form of stimulus-stimulus association,
paired-associate learning. The verbal paired-associate task has been
exceedingly useful in understanding cognitive aspects of associative
learning in humans and is often applied in the assessment of amnesia. It
seemed to us that a paired-associate task adapted for animals was the
simplest paradigm that we could exploit for neurobiological studies on the
learning of new associations between distinct and neutral stimulus events.

The paired-associate task as typically used for humans
involves presentation of a list of arbitrarily paired words followed by
testing in which the subject is cued with the first item of each pair and
must recall the second item. For rats, we designed an analogous task using
odor stimuli and a recognition format that required subjects to
distinguish appropriate odor pairs from a large number of foils .

Rats were trained to perform a nose poke into a sniff
port when a signal light was illuminated. They sniffed two odors presented
in rapid succession, separated by a period when airflow was reversed to
prevent stimulus blending. Four rewarded odor sequences (paired
associates) were composed out of eight different odors (A-B, C-D, E-F,
G-H). When the rat smelled a rewarded pair (in either order, e.g., A-B or
B-A), it could obtain a sweetened water reward from the water port. There
were two kinds of unrewarded "foil" odor sequences. One kind (mispairings)
was composed of the same odors used to form the paired associates but
presented in different combinations, ie.g.. A-C. There were 48 of these
mispair sequences. To distinguish a mispairing from a paired associate,
the rat had to learn the arbitrarily assigned association between the
odors. The other type of foil (nonrelational sequences) involved one of
the odors A through H combined with one of four other odors that was never
associated with reward (W through Z). There were 64 of these nonrelational
sequences. To distinguish a nonrelational sequence from a paired associate
the rat was required only to recognize the never-rewarded odor in the
sequence. The inclusion of both types of foils allowed us to examine in
the same subjects the effects of hippocampal system damage on associative
and nonassociative learning.

We began our experiments on paired-associate learning
by examining the performance of rats in which the parahippocampal region
had been removed, effectively eliminating the contributions of both that
area and the hippocampus itself. lntact rats and rats with parahippocampal
area lesions learned to distinguish nonrelational pairs from paired
associates at the same rate. In addition, normal rats gradually learned to
distinguish paired associates from odor mispairings. By contrast, rats
with parahippocampal lesions could not learn to distinguish paired
associates from mispairings, even when given nearly twice as many training
trials as normal rats. Similar findings of impaired stimulus-stimulus
association have been made in monkeys . In a subsequent study we evaluated
the role of the hippocampus itself in paired-associate learning using the
identical task and testing procedures.

Selective neurotoxic lesions of the hippocampus also
affected paired-associate learning and had no effect on learning
nonrelational sequences. However, by contrast to the severe impairment
observed after parahippocampal region lesions, hippocampal lesions
resulted in a striking facilitation in distinguishing paired associates
from mispairings. This combination of findings indicates that both areas
normally contribute to paired-associate learning, and suggests their
functions are different and perhaps antagonistic. The results led us to
speculate that stimulus representations involved in a paired associate
could be encoded in two fundamentally different and opposing ways, one
subserved by the parahippocampal region and another mediated by the
hippocampus .

One form of encoding could involve the fusion of the
two odor representations just as James described occurs when the items are
not conceptually distinct. More recently and to differing ends, Schacter
characterized this type of representation as a "unitized
structure," and others have referred to such an encoding as a "configural"
representation. Extending our results showing that the parahippocampal
region can maintain persistent stimulus representations, we have suggested
this area can combine items that occur sequentially as well as
simultaneously . In this way the parahippocampal region could mediate the
encoding of the elements of paired associates as fused, unitized, or
configural representations. Alternatively, stimulus elements in paired
associates could be separately encoded and then have their representations
associated in memory. An "association" of this type differs from
a fused representation in that it maintains the compositionality of the
elemental representations and organizes them according to the relevant
relationships among the items. We have previously argued that such
relational representations are mediated by the hippocampal system; based
on the findings on paired-associate Iearning, our current view is that
relational memory processing is mediated specifically by the hippocampus
itself .

To distinguish these two types of stimulus-stimulus
representation we developed two other variants of the paired-associate
paradigm. To speed the rate of learning paired associates, we also adopted
new testing methods that involved more "naturalistic" behaviors
for memory testing. A central feature of our new tasks was that rats were
required to express the memories of odor-odor associations in novel
situations where the learned odor elements were separated and one of them
had to be used to guide behavioral responses that differed from those
involved in the initial learning. Because these demands of memory
expression require a compositional representation, our expectation was
that the hippocampus itself would be required for performance in such
tests of paired-associate learning.

One of these experiments involved a "natural"
form of paired associate Iearning by rats developed by Galef to study the
social transmission of odor selection. He has shown that rats learn from
conspecifics which foods are preferable by experiencing the pairing of a
distinctive (not necessarily novel) food odor with an odorous constituent
of rat's breath (carbon disulfide). Retention of learning in Galef's task
required rats to employ the learned association of the distinctive food
odor to guide subsequent food selection during an explicit choice between
multiple foods. We have recently found that long-term memory for this form
of paired associate learning is blocked by selective neurotoxic lesions of
the entire hippocampus, indicating that the memory for paired associates
does depend on the hippocampus itself in a situation where the relevant
stimulus relationships are set in a "natural" context and memory
expression differs from repetition of the learning event. [Note: This
means that hippocampally impaired people may not do well in dealing with a
new context, a trait necessary for analysis of current situations and a
determination of a response. This would impair an individuals capability
in resisting tyranny or repression].

In addition, to more explicitly examine the flexibility
of memory dependent on the hippocampus itself, we developed another
paired-associate task that was used to assess an animal's ability to infer
relations among associated elements presented in novel configurations . As
described above, animals with selective hippocampal damage can acquire
odor-odor representations in Iearning responses to representations of
specific odor pairings. However, we believe this learning is supported by
fused stimulus representations that are "hyperspecific,"
rendering the animals unable to make flexible and inferential judgments
about the same items when presented in unusual ways. Exploiting rodents'
natural foraging strategies that employ olfactory cues, animals were
trained with stimuli that consisted of distinctive odors added to a
mixture of ground rat chow and sand through which they dug to obtain
buried cereal rewards. On each paired-associate trial one of two sample
odors initially presented was followed by two choice odors each assigned
as the "associate" of one of the samples and baited only when
preceded by that sample. Following training on two sets of overlapping
odor-odor associations subsequent probe tests were used to characterize
the extent to which learned representations supported two forms of
flexible memory expression, transitivity, the ability to judge
inferentially across stimulus pairs that share a common element, and
symmetry, the ability to associate paired elements presented in the
reverse of training order.

Intact rats learned paired associates rapidly and
hippocampal damage did not affect acquisition rate on either of the two
training sets, consistent with recent reports on stimulus-stimulus
association learning in rats and monkeys. Intact rats also showed strong
transitivity across the sets with a preference of ~2:1 in favor of choice
items indirectly associated with the presented sample. By contrast rats
with selective hippocampal lesions were severely impaired in that they
showed no evidence of transitivity. In the symmetry test, intact rats
again showed the appropriate preference of ~3:1 in the direction of the
symmetrical association. By contrast, rats with hippocampal lesions again
were severely impaired showing no significant capacity for symmetry.

These findings provide compelling evidence that some
form of stimulus-stimulus representations can be acquired independent of
the hippocampus itself , although this form of representation is
hyperspecific. Only a hippocampally mediated representation can support
the flexible expression of associations among items within a larger
organization. Collectively. the findings from our studies on
paired-associate learning in animals provide an extension of classic views
on human memory such as William James' description of "memory"
as involving an elaborated network of associations that can be applied
across a broad range of situations, as distinct from "habits"
that depend on rigid associative sequences.

These findings are also entirely consistent with
present day characterizations of human declarative memory such as Cohen's
description of declarative memory as "promiscuous" in its
accessibility by novel routes of expression. Our experiments using a
rodent model of declarative memory show this capacity is dependent on the
circuitry within the hippocampus itself.

Conclusions

In everyday life surely the distinct aspects of
cortical and hippocampal memory processing are intertwined. The prominence
of bidirectional connections between cortical and hippocampal structures
would make it difficult to have parallel coexisting short-lived and
persistent, or fused and associated representations at distinct Ievels of
the system. Rather, as indicated in our characterization of neuronal
firing properties in the olfactory cortex, interactions among these
structures likely results in a unified persistence and form of
representation throughout the system in intact animals. How these
interactions unfold among components of the cortical hippocampal system
should become a main target of interest in studies on the operation of
this system.